Early life stress impairs DG formation by down regulating Autotaxin

描述(申请人提供)：自体趋化蛋白(ATX)是一种分泌型溶血磷脂酶，对胚胎发育期间神经干细胞(NSC)的正常增殖、迁移和存活至关重要。ATX的缺失是胚胎致死的，这解释了缺乏关于其在围产期(出生后1-21天)支持NSC增殖的作用的信息。在这里，我们显示，ATX在海马区(HP)的表达在围产期达到顶峰，当小鼠在此期间暴露于慢性或急性应激时，ATX的表达显著下降。我们还提供了初步数据，21日龄ATX基因杂合子的幼鼠减少了齿状回(DG)的NSC增殖和颗粒细胞层(GCL)的体积。基于这些初步数据，我们假设发育中的幽门螺杆菌ATX的表达对正常的DG发育是必要的(目标1)，恢复暴露于早期生活应激(ELS)的幼鼠的ATX正常水平将阻断ELS对DG发育的抑制作用(目标2)，以及发育中的HP中ATX的表达受到皮质酮水平的快速调节(目标3)。如果得到确认，这项工作将对以前的工作做出三个重要贡献。首先，它将第一次证明正常 在围产期DG的形成需要高水平的ATX表达。其次，它将表明，血浆中的皮质酮水平严格调节发育中的幽门螺杆菌的ATX水平。第三，它将提供一种新的分子机制来解释围产期暴露于压力如何影响DG的发育。我们预测ATX在人类DG的发展中扮演着类似的角色，这项工作将确定一条关键的途径，通过这条途径，早期的虐待和忽视会导致成年人类Hp的长期功能障碍。。

DESCRIPTION (provided by applicant): Autotaxin (ATX) is a secreted lysophospholipase that is essential for normal proliferation, migration, and survival of neural stem cells (NSC) during embryonic development. Deletion of ATX is embryonic lethal explaining the lack of information regarding its role in supporting NSC proliferation during the perinatal period (postnatal days 1-21). Here we show that expression of ATX in the hippocampus (HP) peaks during the perinatal period and is dramatically decreased when mice pups are exposed to chronic or acute stress during this period. We also present preliminary data that 21-day old pups that are heterozygous for the ATX gene have reduced NSC proliferation in the dentate gyrus (DG) and a decrease in granule cell layer (GCL) volume. Based on these preliminary data we hypothesize that ATX expression in the developing HP is essential for normal DG development (aim 1), that restoring normal levels of ATX to pups exposed to early life stress (ELS) will block the inhibitory effect that ELS has on DG development (aim 2), and that ATX expression in the developing HP is rapidly regulated by corticosterone levels (aim 3). If confirmed, this work will make three important contributions to previous work. First, it will demonstrate for the first time that normal DG formation, during the perinatal period, requires high expression levels of ATX. Second, it will show that corticosterone levels in the plasma tightly regulate ATX levels in the developing HP. Third, it will provide a novel molecular mechanism to explain how exposure to stress, during the perinatal period, affects DG development. We predict that ATX plays a similar role in DG development in humans, and that this work will identify a critical pathway by which abuse and neglect early in life cause long-term dysfunction in the HP of adult humans. .